Since the discovery of the physiological roles of nitric oxide (NO), much research has focused on the synthesis of NO-releasing materials/vehicles to elicit NO's characteristics as an antimicrobial agent, mediator of wound repair, or angiogenic cofactor. S-Nitrosothiols (RSNOs) are one class of endogenous NO donor believed to store/transport the majority of the body's natural reservoir of NO. As such, a large body of work has utilized low molecular weight RSNOs (e.g., S-nitroso-glutathione (GSNO), S-nitroso-N-acetylcysteine (SNAC), and S-nitroso-N-acetyl-penicillamine (SNAP)) as donors to spontaneously release NO. Although promising, the clinical application of low molecular weight NO donors has been slow due to both lack of tissue specific targeting and uncontrollable NO release kinetics. To address such shortcomings, NO donor precursors have been conjugated to larger scaffolds (e.g., proteins, dendrimers, and nanoparticles), thus enabling high NO storage per delivery vehicle and release profiles similar to their small molecule analogues.
Silica particles are among the most widely employed macromolecular scaffolds for biomedical applications due to facile synthetic strategies and minimal cytotoxicity. Previously, the surface of fumed silica particles (7-10 nm diameter) have been grafted with SNAP, SNAC, and S-nitrosocysteine (CysNO) to create S-nitrosothiol-modified silica particles. However, the NO storage was limited to 0.021-0.138 μmol mg−1 because the thiol functionalization was restricted to the exterior of the particle. Additionally, these systems are not able to tune particle size to fit a therapeutic system of interest. Alternatively, the hydrolysis and co-condensation of organosilane and tetraalkoxysilane precursors via sol-gel chemistry may represent a method for preparing a silica network with a higher concentration of organic functionalites. Indeed, the Stöber process (sol-gel chemistry with an alcohol solvent and an ammonia catalyst) has proven effective for synthesizing N-diazeniumdiolate-modified silica particles of diverse size and NO storage capacity. See, for example, U.S. Publication No. 2009/0214618 (Schoenfisch et al.), which is herein incorporated by reference in its entirety. The advantage of the Stöber method over surface grafting is that the co-condensation provides uniform incorporation of the organic (i.e., NO donor) functionality throughout the resulting silica network as opposed to restricted functionalization at the surface alone. As a result, such particles may exhibit significantly increased NO storage.